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New Cloud over Clinical Trial Led by FDA Nominee

Robert Califf FDA

A clinical trial co-chaired by President Obama’s nominee to head the FDA was compromised by flawed test readings, lawyers for patients have alleged in litigation against a drug company.

The Project On Government Oversight has previously reported that a clinical trial of the blood thinner Xarelto suffered from a potentially crippling flaw: It relied on a brand of blood-testing device with a record of delivering false results.

Now, lawyers with access to non-public data from that trial are alleging that problems with the testing devices affected the trial results.

Documents under seal in litigation over the drug indicate there were discrepancies between measurements taken with the devices in the clinical trial and other measurements, lawyers for patients allegedly harmed by Xarelto said in a court filing Friday.

The documents indicate that, based on such discrepancies, the testing devices used in the trial failed to meet an international performance standard, according to the court filing.

“An astonishingly high percentage” of the blood test readings in the trial “were shown to be out of range,” the filing said.

The results of the clinical trial “are invalid and call into question the approval of this drug,” the filing said.

The Friday filing asked a federal court to force Johnson & Johnson, which co-sponsored the clinical trial and markets Xarelto in the United States, to turn over documents that could shed light on how, if at all, any malfunctioning of the testing devices affected the trial results. The filing said Johnson & Johnson and affiliated companies—defendants in the litigation—have refused to provide those records to the plaintiffs.

The dispute calls into question the work of Robert Califf, whose nomination to be FDA commissioner is awaiting a vote by the full Senate, and the FDA’s oversight of a drug now in widespread use.

More than four years ago, the FDA approved Xarelto to prevent blood clots and strokes in patients with atrial fibrillation, a condition that involves irregular beating of the heart. The drug, which may be familiar to television viewers from ads featuring comedian Kevin Nealon and golfer Arnold Palmer, has generated billions of dollars of sales for Johnson & Johnson and Bayer, which makes the drug and markets it in other countries.

The drug has been approved for other conditions based on other studies.

The FDA based its approval of Xarelto for atrial fibrillation on a clinical trial called ROCKET AF that involved more than 14,000 patients in 45 countries over several years. The trial was coordinated by the Duke Clinical Research Institute, which tests drugs for pharmaceutical companies. Califf, who is now a deputy commissioner at the FDA, founded that institute and co-chaired the ROCKET AF executive committee.

The trial compared Xarelto to warfarin, a blood thinner that has been in use since the 1950s. Patients on warfarin are supposed to have their blood tested regularly to make sure it is neither too thick nor too thin. If it’s too thick, they are at heightened risk of developing blood clots, which can cause strokes and other fatal consequences. If it’s too thin, they are at heightened risk of suffering bleeds, including bleeding in the brain. Doctors use the blood test results to adjust patients’ doses and keep their clotting rates, known as INRs, in the desired range.

Blood testing devices of the make used in the ROCKET AF trial were the subject of two FDA warning letters before the trial began and an FDA recall notice after the trial ended. The recall notice said devices marketed under the INRatio name could deliver falsely low test results with potentially deadly consequences.

In the court filing Friday, lawyers suing Johnson & Johnson over Xarelto argued that falsely low test results would lead to trial subjects in the warfarin group being given too much of that blood thinner, causing them to suffer more bleeding.

“[M]any of the bleeds in the warfarin arm were caused by inappropriate dosing," the court filing said. If not for the inappropriate dosing, "it would have been shown that Xarelto was inferior to warfarin when comparing the risk of a bleeding event,” the filing said.

The court filing cited a document under seal whose title suggests it compared clotting rates measured with the INRatio devices to INR rates determined by laboratories. The document was cited as “Table of Discrepancies Between Lab Based INR and Device Based INR.” The ROCKET AF protocol said that, at certain points in the trial, parallel lab tests would be performed.

Responding to an inquiry from POGO, the Duke Clinical Research Institute (DCRI) said in November that it was reanalyzing data from the trial. In December, a year after the FDA recall, the ROCKET AF executive committee said that, in light of the 2014 recall, it had conducted a new analysis of trial results. “The findings from the analysis are consistent with the results from the original trial and do not alter the conclusions of ROCKET AF,” a statement posted by DCRI said. Xarelto “is a reasonable alternative to warfarin and is non-inferior for the prevention of stroke and systemic embolism with less intracranial hemorrhage and fatal bleeding,” the statement said.

The Duke statement and the court filing mentioned different aspects of the clinical trial results. The court filing focused on a broad set of problems measured in the trial—bleeding events. The Duke statement listed such categories as intracranial hemorrhage—bleeding within the skull—and fatal bleeding, but it did not specifically mention the broader category of bleeding events.

Responding to questions for this story, a spokesman for Janssen, a subsidiary of Johnson & Johnson, said Xarelto “is an important anticoagulant.”

“Bayer and Janssen have conducted a number of sensitivity analyses, which confirm the results of the ROCKET AF study and the positive benefit-risk profile of XARELTO® (rivaroxaban) in patients with non-valvular atrial fibrillation,” Janssen spokesman William Foster said by email.

“After more than three years on the U.S. market, and more than 3 million patients prescribed in the U.S. to date, the benefit-risk profile of XARELTO® remains favorable and consistent with clinical trials,” Foster said.

“We will continue to defend against the claims raised in this litigation,” he added.

The FDA has said it is reviewing data, and its counterpart the European Medicines Agency (EMA) has said it is investigating. “Due to the defect, it is now thought that the INR device may have impacted the clotting results in some patients in the warfarin group,” EMA spokeswoman Rebecca Harding said in a December email to POGO.

The records the plaintiffs’ lawyers are seeking in court include documents related to DCRI’s reanalysis of trial results and documents submitted to the EMA as part of the European regulator’s investigation.

“Internal email correspondence demonstrates that Defendants sought to unduly narrow the focus of the analyses and clarifications sought by EMA by assessing the impact only on a small subgroup of patients . . . rather than engaging in a more broad and thorough assessment of all patients in the clinical trial,” the Friday court filing said.

The statement DCRI issued in December said the new analysis focused on the effect of possible malfunctioning of the device “in specific patient groups.” The FDA recall notice said devices could yield incorrect results in patients with certain medical conditions, but it also indicated that the devices could malfunction in patients outside those groups.

Califf and a spokeswoman for DCRI did not respond to emails for this article.

DCRI, which is not a defendant in the litigation, has posted only a one-sentence summary of its reanalysis. According to another recent court filing by plaintiffs’ lawyers, the reanalysis has been submitted to a peer-reviewed journal for publication.

According to a memorandum the plaintiffs filed in court January 11, the defendants have refused to produce documents related to the DCRI reanalysis for use in the litigation on the grounds that “the peer-review process could well result in further analysis, correction and/or revisions to the conclusions in the reanalysis.”

Read our report, “Drug Problems: Dangerous Decision-Making at the FDA

Read more articles in the “Drug Problems” series

By: David S. Hilzenrath
Chief Investigative Reporter, POGO

David Hilzenrath David Hilzenrath is the Chief Investigative Reporter for the Project On Government Oversight.

Topics: Public Health and Science

Related Content: Food and Drug Administration, Drug Problems

Authors: David S. Hilzenrath

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